Cannabis is the most widely used illicit drug in the world and in the United States. Currently, no effective pharmacological treatment has been found for treatment of cannabis dependence. Here, we will evaluate for the first time in a pilot study the potential of using a cannabinoid medication (SATIVEX(R);approved for medical use in Canada) as a substitution therapy for cannabis dependence. The objectives of our study are: i) To compare cannabis use in subjects receiving 12 weeks SATIVEX(R) Spray associated with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT) intervention vs. subjects receiving 12 weeks Placebo Spray associated with MET/CBT intervention;ii) To compare ratings of cannabis cravings and withdrawal in subjects receiving 12 weeks SATIVEX(R) Spray associated with MET/CBT intervention vs. subjects receiving 12 weeks Placebo Spray associated with MET/CBT intervention;iii) To collect biological samples (urine samples three times weekly and plasma sample weekly) and collaborate with scientists within the NIDA-IRP to determine the ability of measuring cannabinoids in those biological samples to assess exposure to licit (SATIVEX(R)) or illicit cannabinoids (cannabis) during the course of the study. This pilot two-year study will evaluate the tolerability and collect information on efficacy of SATIVEX(R) in 45 subjects. 5 subjects will be treated using an open-label design and 40 subjects using a randomized, double-blind, placebo-controlled design for cannabis dependence in n=40 ambulatory subjects (20 subjects on SATIVEX(R) and 20 subjects on placebo). The medication phase of the trial will continue for a total of 12 weeks, concurrent with weekly sessions of combined Motivational Enhancement Therapy and Cognitive-Behavioral Therapy (MET/CBT) for both groups. There will be follow up until 6 months after the target quit date. Outcomes measures will include abstinence from cannabis use, reduction in amount of cannabis used, as well as craving/withdrawal and other psychiatric symptoms. Multiples blood and urine sample will be analyzed in collaboration with scientists from the intra-mural research program of NIDA. PUBLIC HEALTH RELEVANCE: Cannabis dependence is a leading physical and mental health concern. To date, there have been no pharmacological treatments found to be effective in preventing relapse in cannabis dependence. The present project will evaluate a promising pharmacological treatment for the treatment of cannabis dependence.